Exosomal miR-146a-3p modulates neural stem cell fate through UCHL1 downregulation in spinal cord injury: implications for neuroregeneration

Spinal cord injury (SCI) poses a substantial challenge within the field of regenerative medicine, primarily because of its high incidence of disability and the paucity of effective therapeutic interventions. This study explores the involvement of cerebrospinal fluid (CSF) exosomes in the differentiation of neural stem cells (NSCs) following SCI, with a particular emphasis on the miR-146a-3p/UCHL1 signaling axis. Using an SCI animal model, we analyze the molecular composition of CSF and its influence on NSC fate through bioinformatics approaches, dual-luciferase reporter assays, and <i>in vitro</i> differentiation experiments. Differential expression analyses reveal a significant upregulation of miR-146a-3p in CSF-derived exosomes post-SCI, which directly targets and suppresses UCHL1, a pivotal regulator of neuronal differentiation. Overexpression of UCHL1 facilitates the differentiation of NSCs into neurons and enhances functional recovery, whereas its downregulation leads to increased astrocytic differentiation and fibrotic scar formation. These findings are corroborated through immunofluorescence, western blot analysis, and behavioral assessments. In summary, our study identifies miR-146a-3p as a critical regulator in SCI, offering novel insights into the role of microRNAs in modulating neural stem cell fate and promoting neuronal regeneration. Our study highlights the pivotal role of CSF exosomal miRNAs in determining NSC fate, paving the way for systemic interventions in injured spinal cord injury repair. These findings underscore the importance of exosomal miRNAs in modulating the spinal cord microenvironment, potentially leading to novel strategies for enhancing functional recovery in SCI patients.